Dataset Information

Excitation Energy Migration Unveils Fuzzy Interfaces within the Amyloid Architecture.

ABSTRACT: Amyloid fibrils are highly ordered nanoscopic protein aggregates comprising a cross-β amyloid core and are associated with deadly human diseases. Structural studies have revealed the supramolecular architecture of a variety of disease-associated amyloids. However, the critical role of transient intermolecular interactions between the disordered polypeptide segments of protofilaments in directing the supramolecular structure and nanoscale morphology remains elusive. Here, we present a unique case to demonstrate that interchain excitation energy migration via intermolecular homo-Förster resonance energy transfer can decipher the architecture of amyloid fibrils of human α-synuclein. Site-specific homo-Förster resonance energy transfer efficiencies measured by fluorescence depolarization allowed us to construct a two-dimensional proximity correlation map that defines the supramolecular packing of α-synuclein within the fibrils. These studies captured unique heteroterminal cross talks between the fuzzy interprotofilament interfaces of the parallel-in-register amyloid spines. Our results will find applications in discerning the broader role of protein disorder and fuzziness in steering the distinct polymorphic amyloids that exhibit strain-specific disease phenotypes.

SUBMITTER: Majumdar A

PROVIDER: S-EPMC7264808 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Excitation Energy Migration Unveils Fuzzy Interfaces within the Amyloid Architecture.

Majumdar Anupa A Das Debapriya D Madhu Priyanka P Avni Anamika A Mukhopadhyay Samrat S

Biophysical journal 20200423 11

Amyloid fibrils are highly ordered nanoscopic protein aggregates comprising a cross-β amyloid core and are associated with deadly human diseases. Structural studies have revealed the supramolecular architecture of a variety of disease-associated amyloids. However, the critical role of transient intermolecular interactions between the disordered polypeptide segments of protofilaments in directing the supramolecular structure and nanoscale morphology remains elusive. Here, we present a unique case ...[more]

PMID: 32402242

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Project description:Amyloids, large intermolecular sandwiched β-sheet structures, underlie several protein misfolding diseases but have also been shown to have functional roles and can be a basis for designing smart and responsive nanomaterials. Short segments of proteins, called aggregation-prone regions (APRs), have been identified that nucleate amyloid formation. Here we present the database of 173 APR crystal structures currently available in the PDB, and a tool, ACW, for analyzing their topologies and the 267 inter-β-sheet interfaces of zipper regions assigned in these structures. We defined a new descriptor of zipper interfaces, the surface detail index (SDi), which quantifies the intertwining between the side chains of both β-sheets of the zipper, an important factor for the molecular recognition and self-assembly of these mesostructures. This allowed a comparative analysis of the zipper interfaces and identification of 6 clusters with different intertwining, steric fit, and size characteristics using three complementary descriptors, SDi, shape complementarity, and buried surface area. 60% of the APR structures are formed by parallel β-sheets, of which 52% belong to the topological class 1. This could be explained by the better fit and a deeper entanglement of the zipper regions of the parallel structures than of the antiparallel structures, as the analysis showed that both their shape complementarity (0.79 vs 0.70) and SDi (1.53 vs 1.32) were higher. The higher abundance of certain residues (Asn and Gln in parallel and Leu and Ala in antiparallel β-sheets) can be explained by their ability to form different ladder-like secondary interaction patterns within β-sheets. Analogous to the hierarchy of protein structure, we interpreted the primary, secondary, tertiary, and quaternary structure levels of APRs revealing different characteristics of the zipper regions for both parallel and antiparallel β-sheet structures, which may provide clues to the structural conditions of amyloid core formation and the rational design of amyloid polymorphs.

Dataset Information

Excitation Energy Migration Unveils Fuzzy Interfaces within the Amyloid Architecture.

Publications

Excitation Energy Migration Unveils Fuzzy Interfaces within the Amyloid Architecture.

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